Niemann-Pick disease type C1 is an autosomal recessive, neurodegenerative disease with a frequency of one in 120,000 live births. Approximately 95 percent of cases are caused by mutations of the NPC1 gene, and the remaining 5 percent are caused by mutations in the NPC2 gene. Mutations that produce defective NPC1 protein, a cholesterol trafficking protein, lead to accumulation of unesterified cholesterol and other lipids in lysosomes. Manifestations of the disease include neonatal jaundice, splenomegaly, ataxia, and progressive neurodegenerative impairment of motor and intellectual function. Most often, the onset of symptoms occurs in early childhood, leading to death within a decade. Currently, no therapies have been approved by the Food and Drug Administration (FDA) for this progressively fatal neurodegenerative disease. The molecule 2-hydroxypropyl-beta-cyclodextrin (HPBCD) has been shown to reduce both cholesterol and sphingolipid storage and to prolong survival in two types of Niemann-Pick type C1 animal models. The goal of this project is to provide the preclinical studies and clinical tools needed to establish safe and effective dosing regimens for treatment of human subjects with HPBCD. TRND established an interdisciplinary project team of academic and industrial scientists from nine different organizations and received ongoing input from patient advocacy groups in order to accomplish the clinical evaluation of HPBCD most efficiently. TRND scientists conducted the animal toxicology studies necessary to file an Investigational New Drug (IND) application with the FDA and helped support biomarker studies. TRND provided regulatory support to achieve clearance of the IND application with the FDA in November 2012, and first-in-human clinical trials began in January 2013 at the NIH Clinical Center. Due to the strong preclinical and early clinical data, including the Phase 1 trial, the program was licensed to a company, Vtesse Pharma, and received the FDA's Breakthrough Therapy Designation. This designation could accelerate approval to provide the first effective treatment for slowing the progress or stabilizing the devastating impacts of NPC in children and adolescents. The Phase 1 trial was concluded successfully, and currently, the drug is being tested in a multicenter, multinational Phase 2b/3 clinical efficacy trial.